Oligo- and polysaccharides containing uronic acid building blocks such as the glycosaminoglycans heparin, heparan sulfate, chondroitin sulfate and dermatan sulfate have important physiological functions, for instance they may have antithrombotic activity. Such compounds may be isolated from biological sources such as intestinal mucosa, but may also be prepared synthetically.
This generally requires a multi-step synthesis. A key step in this synthesis is the oxidation of primary hydroxyl groups of (intermediate) oligosaccharides to carboxylic acids without affecting either the unprotected secondary hydroxyl groups or the protection of other hydroxyl groups also present in the molecule.
In most methods known in the art for the oxidation of oligosaccharides, such as chromium based oxidation reactions, selective oxidation of the primary hydroxyl groups is not possible. Those reactions require also protection of the secondary hydroxyl groups, which would otherwise be left unprotected. As a result, the selective oxidation of primary hydroxyl groups of oligosaccharides using those known methods needs more than one reaction step (involving protection of the secondary hydroxyl groups, oxidation of the primary hydroxyl groups, and deprotection of the secondary hydroxyl groups).
However, Davis, N. J. and Flitsch, S. L. (Tetrahedron Letters, Vol.34, 1181-1184 (1993)) describe a one-step process of selective oxidation of primary hydroxyl groups of partially protected monosaccharides to their carboxylic acids. The reaction is performed in a two-phase solvent system (dichloromethane and water) using sodium hypochlorite as the oxidant in the presence of catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). A serious drawback of this process is that it has been found not to be suitable for oligosaccharides comprising more than one saccharide unit. In such cases the oxidation does not fully proceed to form the desired carboxylic acids. Further, a synthetic disadvantage is the two-phase solvent system which requires a phase transfer catalyst.
Also another process for the complete and selective oxidation of primary alcohols of oligo- and polysaccharides was reported (WO 95/07303). However, this process is only successful with unprotected oligosaccharides. For the oxidation also a hypohalite is used and a catalytic amount of a di-tertiary-alkyl nitroxyl, however in an aqueous medium at pH of 9-13. This latter process is unfavourable for the oxidation of protected oligosaccharides, since the protection does not remain intact under these highly basic conditions. Further, large amounts of salts are formed in this reaction, the removal of which is in particular a problem in the case of smaller oligosaccharides (see e.g. De Nooy, A. E. J et al. in Receuil des Travaux Chimiques des Pays Bas, 113/03, March 1994).